7. PROJECT SUMMARY Understanding how human cells organize, shape, and move their membrane-bound organelles is one of the most fundamental problems in biology. To address this challenge, my laboratory studies how the actin and microtubule cytoskeletons control membrane remodeling and organelle dynamics. As cells age, their ability to properly regulate these processes changes. This is especially true for kidney cells and immune cells, as a variety of renal and inflammatory diseases develop with age. However, the differences in cytoskeletal functions that give rise to these cellular changes during the aging process are poorly understood. In human cells, actin filament networks are assembled by proteins called nucleation factors from the Wiskott-Aldrich Syndrome Protein (WASP) family. Despite their importance in remodeling membranes during a wide range of processes, these nucleation factors have not been well characterized, especially as they relate to aging and mechanisms of human disease. I have a long-standing interest in determining how the cytoskeleton drives membrane dynamics in normal cells, and how these functions are altered in the context of infectious and genetic diseases. The immediate goal of this Career Development Award is to allow me to initiate another avenue of investigation on the role of the cytoskeleton in cell aging so that I can achieve my long-term goal of leading a lab which studies cytoskeletal functions in health, aging, and disease. These goals will be achieved by completing four specific aims: (1) Define roles for actin nucleation factors and regulators of autophagy in kidney disease, including Nephrocerebellar Syndrome (NCS); (2) Determine functional links between the cytoskeleton, autophagy, cytokine secretion, and inflammation during infection and aging; (3) Deepen my training in the biology of aging through collaborative training experiences at the Jackson Laboratory's Nathan Shock Center of Excellence in the Basic Biology of Aging and at the Center on Aging at the UConn Health Center; (4) Develop into an independent investigator in the basic biology of cell aging. Given my expertise in cytoskeletal biology, plus my existing grant on the role of actin nucleation in autophagy and disease, my lab is uniquely positioned to provide key mechanistic insights into the relationships among actin nucleation factors, autophagy, kidney function, inflammation, and aging.